Accelerated, Left Prefrontal Transcranial Magnetic Stimulation for Functional Seizures; An Open-Label Exploration of Feasibility, Tolerability, and Preliminary Efficacy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Percentage of Participants Completing TMS Sessions
研究概览
简要总结
The purpose of this project is to assess the feasibility, tolerability, and preliminary efficacy of using an accelerated, intermittent theta burst stimulation (a-iTBS-rTMS) protocol targeting the left dorsolateral prefrontal cortex (l-dlPFC) for Psychogenic Non-Epileptic Seizures (PNES) or Seizure-Type Functional Neurologic Disorder (FND-seiz) in an open-label fashion. Following screening, consent, and enrollment, participants will receive 6-to-10 iTBS-rTMS sessions per day (i.e., theta burst; 600 pulses per session; 6000 pulses per day) over a 3-to-5 treatment days with a target of 30 total sessions (18,000 total pulses). TMS will be targeted to Beam F3 for comparison to the bulk of the literature and to most mimic replicable and clinical use. This proposed iTBS-rTMS protocol was chosen given its previously shown safety, tolerability, and effectiveness in other conditions, but also as it has the potential to shorten treatment to only 3 days, which investigators theorize will be more feasible for patients with FND-seiz.
Feasibility will be measured as the percentage of participants who receive at least 20 treatment sessions within the 3-to-5-day window. Other than self-assessments used in the safety screening process or to monitor TMS benefits and risks, secondary subjective measures will assess previously investigated FND-seiz-specific outcomes, which will be obtained prior to intervention and 4-weeks post-intervention. In addition to monthly seizure frequency, this will include validated measures regarding stigma, health-related QOL, depression, PTSD, somatic symptoms, psychosocial functioning, psychological distress, and clinical and participant impression of improvement and satisfaction. Sub-analysis will further divide participants with mild to no depression and/or PTSD versus moderate to severe depression and/or PTSD to further assess how the TMS effects known to effect other highly comorbid disorders with FND-seiz, may indirectly affect FND-seiz outcomes.
详细描述
Seizure-Type Functional Neurologic Disorders (FND-seiz) are strikingly prevalent-accounting for 5-15% of epilepsy center referrals and up to 40% of epilepsy monitoring unit admissions-when considering the associated barriers to treatment and dismal outcomes. Due to resource-intensive requirements, diagnosis is often delayed by years. In the interim, patients frequently receive inappropriate antiseizure medications and have high utilization of emergency services. Years after diagnosis, many FND-seiz patients continue to experience non-epileptic seizures (NS) and have high rates of disability. Due to stigma and psychosocial barriers, engagement and responses to the standard of care, Cognitive Behavioral Therapy (CBT), are inconsistent. As many patients are told they may have epilepsy prior to receiving an accurate diagnosis, there is an obvious disconnect between the recommended psychological treatment and the physical nature of their symptoms, which can limit acceptance of the diagnosis and subsequently CBT engagement. Furthermore, the only powered RCT (the CODES trial) examining CBT in FND-seiz failed to show a significant seizure reduction at 12 months follow up and the overall effect size was lower than previously thought highlighting the limitations of a "one-size-fits-all" model for a highly comorbid disorder. Ultimately, patients with FND-seiz have been found to have a poorer overall quality of life compared to epilepsy and a standardized mortality rate 2.5 times greater the general population and comparable to that of drug-resistant epilepsy
Together these factors underscore the need for alternate treatments capable of addressing psychosocial challenges unique to FND-seiz or further investigating the underlying neurobiology. Investigators theorize that offering a brain-network based approach may reduce stigma associated with confusion over the "psychological" rather than "neurological" etiologic conception of FND-seiz, which if effective, may be a more feasible for some patients. Brain-imaging research and prior reports of benefit with neurostimulation suggests TMS to the left dorsolateral prefrontal cortex (l-dlPFC) has the potential to improve cortico-limbic or cortico-sensorimotor governance, which Investigators theorize in FND-seiz may decrease NS frequency or improve quality of life. Thus, Investigators aim to investigate the feasibility and tolerability of an accelerated, intermittent theta-burst TMS protocol in FND-seiz to best mimic current clinical trends and optimize TMS feasibility, which may have several applications for the FND-seiz population.
In clinical practice, the known, but rare risk of inducing an epileptic seizure with TMS and the difficulty differentiating epileptic from non-epileptic seizures, may decrease the comfort of TMS providers to use TMS in FND-seiz patients when indicated for other disabling disorders. In tandem with exploring the feasibility and tolerability of this intervention, Investigators hope to employ and investigate an informed safety protocol, with input from experts in the fields of epilepsy and brain stimulation. Helping providers safely screen patients, more decisively exclude patients with an inaccurate diagnosis or concomitant epilepsy and having a protocol to follow when treating FND-seiz patients who experience a NS during TMS stimulation may increase TMS access for FND-seiz patients with other TMS indications. Finally, as preliminary evidence here at MUSC also suggests combining TMS with CBT for other indications may have a synergistic effect and improve attrition with CBT, if TMS is preliminarily efficacious alone in FND-seiz specific outcomes in a small, open-label sample, this investigation may also help optimize future methodologies examining the use of TMS in FND-seiz.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •>18 years old and <65 years old
- •English Speaking, can read and write, and able to provide informed consent
- •Diagnosis of "documented" Functional Seizures as made by an MUSC epileptologist or neurologist using the ILAE recommendations: "by clinician experienced in diagnosis of seizure disorders (on video or in person), showing semiology of typical of FND-seiz, while on EEG plus no epileptiform activity on routine or ambulatory ictal EEG during a typical ictus/event in which the semiology would make ictal epileptiform EEG activity expected during equivalent epileptic seizures"2
- •In addition to meeting ILAE minimum requirements for FND-seiz diagnosis, must have previously undergone and documented in the electronic medical record a minimum of 24-hours of otherwise normal video EEG without interictal epileptiform findings
- •Duration of symptoms >3 months and continuing to experience NES at least monthly
- •Not currently undergoing any psychotherapeutic intervention, agree to forgo any psychotherapeutic intervention during the study, and if previously completed any psychotherapeutic intervention continue to experience monthly non-epileptic seizures
- •If on psychotropic medications may choose to continue during the duration of the study at current doses, but consent to not modifying medication doses or switching to alternative psychotropic regimens during the trial
- •In good general health, as ascertained by medical history
- •Females of reproductive age (ages 18 to 50) must have a negative urine pregnancy test, performed onsite, and documented in the study record within 72 hours prior to the first TMS session
排除标准
- •History of clinical concern for concomitant epileptic seizures or epilepsy
- •History of ongoing psychosis, mania, active alcohol or substance use disorder as screened by the PSQ, YMRS, AUDIT, and DAST-10
- •History of positive screening urine test for drugs of abuse within the last year: cocaine, amphetamines, barbiturates, opiates
- •Active suicidal intent or a score >2 on question 3 of the HAM-D
- •Use of medications known to lower the seizure threshold at doses that may increase this risk in the setting of rTMS-iTBS (i.e. buproprion at >300 mg, combinations of tricyclic antidepressants, antipsychotics… as determined by investigators)
- •History of central nervous system surgeries or clinically relevant structural brain lesions
- •Significant or unstable cardiac, metabolic, oncologic, psychiatric, developmental, or neurologic condition(s) or treatments that may impact safe participation in the study as determined by the study investigators (e.g. poorly-controlled heart failure, current or past cardiac arrhythmia, sustained systolic blood pressure >180, labile diabetes, significant electrolyte abnormality, brain cancer, cognitive impairment, neurodevelopmental disorders, autism spectrum disorder, mania, schizophrenia spectrum or other psychotic disorder, movement disorders, multiple sclerosis, moderate to severe brain injury)
- •Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation
- •History of TMS exposure
- •TMS contraindications (e.g., ferromagnetic implants, cochlear implants, conditions or treat-ments that lower seizure threshold - as determined by study investigators).
- •Current pregnancy or desire to become pregnant during study duration without contraceptive plan
- •Are a prisoner or in police custody at the time of eligibility screening
结局指标
主要结局
Percentage of Participants Completing TMS Sessions
时间窗: Assessed daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.
Description: Feasibility will be measured as the percentage of participants who complete at least 20 rTMS-iTBS treatment sessions within the 3-to-5-day treatment period. Unit of Measure: Percentage (%) Time Frame: Assessed daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit. Rationale: This measure focuses on the proportion of participants able to adhere to the intensive TMS protocol, a key indicator of feasibility. The time frame is now specific, covering the treatment days (Day 1 to Day 5) and the 4-week follow-up for final reporting.
Session Delivery Patterns
时间窗: Recorded daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.
Description: The number of total rTMS-iTBS sessions delivered will be recorded and analyzed to characterize protocol adherence and delivery patterns. rTMS-iTBS sessions within the protocol are aimed to be delivered over the 3-5 treatment days, during which participants may choose between 6-10 day treatment sessions per day if tolerable and feasible (total of 30 sessions to complete the rTMS-iTBS protocol) Unit of Measure: The number of sessions delivered, represented as a continuous, numerical value. Rationale: This measure provides additional detail on how the protocol is implemented, addressing potential variability in session delivery to assess overall tolerability, feasibility, and analyze any potential adverse events. It further helps inform measures of efficacy if participants do not complete the total session target or complete the course of different time periods (ie, over 4-5 days or over 3 days).
Adverse Event Rate
时间窗: Assessed daily from Day 1 to Day 5 of the TMS treatment period, at the initial screening visit (baseline), and at the 4-week follow-up visit.
Description: Tolerability will be assessed by calculating the percentage of participants experiencing at least one adverse event (AE) related to the rTMS-iTBS protocol, such as headache, scalp discomfort, or dizziness. Adverse events will be recorded and classified using a standardized checklist based on common TMS-related side effects. Unit of Measure: Percentage (%) of participants with at least one AE. Rationale: This measure quantifies the proportion of participants experiencing AEs, providing a clear indicator of the protocol's tolerability. Daily assessments during treatment capture immediate side effects, while the 4-week follow-up evaluates any delayed or persistent effects.
Serious Adverse Event Rate
时间窗: Assessed daily from Day 1 to Day 5 of the TMS treatment period, at the initial screening visit (baseline), and at the 4-week follow-up visit.
Description: Serious adverse events (SAEs), defined as any event resulting in hospitalization, life-threatening conditions, or significant disability (e.g., seizure), will be tracked and reported as the percentage of participants experiencing at least one SAE related to the rTMS-iTBS protocol. Unit of Measure: Percentage (%) of participants with at least one SAE. Rationale: This measure ensures monitoring of severe outcomes, which is critical for assessing the safety of the TMS protocol. The specific time points align with the study's schedule, ensuring comprehensive tracking of rare but serious events.
Pulses per Session Delivery Patterns
时间窗: Recorded daily from Day 1 to Day 5 of the TMS treatment period and summarized at the 4-week follow-up visit.
Description: The number and frequency of rTMS-iTBS pulses delivered over the 3-5 treatment days during which participants may choose between 6-10 day treatment sessions per day. This will be recorded and analyzed to characterize protocol adherence and delivery patterns. A pulse is defined as a burst of three magnetic pulses delivered in quick succession. One treatment session entails 190s encompassing 600 pulses per session. An intermittent theta-burst pulse is defined as a burst of three magnetic pulses delivered in quick succession. The end point of 30 treatment sessions is 18,000 total pulses delivered, which over the 3 to 5 day window can be achieved with 3,600 daily pulses for 5 days or up to 6,000 daily pulses over 3 days. Unit of Measure: The number of sessions delivered, represented as a continuous, numerical value. Rationale: This measure provides additional detail on how the protocol is implemented, addressing potential variability in session delivery to assess overall tole
次要结局
- Non-epileptic Seizure Frequency (NES)(Assessed prior to intervention at visit 1, 2-4 weeks prior to starting the 3-5 day TMS treatment protocol, and at the final follow up visit 4 weeks after completing the TMS treatment protocol.)
- Chronic Illness Anticipated Stigma Scale (CIASS)(Assessed at initial visit (time point 0 at visit 1, 2-4 weeks pre-TMS) and at post-intervention follow-up (4 weeks post-TMS).)
- Montgomery-Asberg Depression Rating Scale (MADRS)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- PROMIS®-29+2 Profile v2.1 (PROPr)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- Patient Health Questionnaire-15 (PHQ-15)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- Clinical Outcomes in Routine Evaluation (CORE-10)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- Clinical Global Impression-Improvement and Severity (CGI-I and CGI-S)(Time Frame: CGI-S assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS); CGI-I assessed only at follow-up (4 weeks post-TMS).)
- The National Hospital Seizure Severity Scale (NHS3)(Assessed at initial visit (2-4 weeks pre-TMS) and follow-up (4 weeks post-TMS).)
- Participants with Complete NES Remission(Assessed at follow-up (4 weeks post-TMS).)
- Participants with >50% Reduction in NES Frequency(Assessed at follow-up (4 weeks post-TMS).)
研究者
Joseph Chasen
Principle Investigator, Resident Physician, MUSC Departments of Psychiatry and Neurology
Medical University of South Carolina